Gene

Excitatory postsynaptic potential

Gene expression

Psychology

Transcriptome

Neuroscience

Cognition

Inhibitory postsynaptic potential

Oligodendrocyte

Myelin

Prefrontal cortex

Central nervous system

Biochemistry

Biology

Nature Neuroscience

Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment. Single-nucleus transcriptomics reveal brain alterations associated with major depression. Deep layer excitatory cells and immature oligodendrocytes showed most changes, involving synaptic plasticity, immune function and steroid hormones.

Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons